While numerous pre-clinical studies have supported the benefit of hormone therapy in reducing the incidence of age-associated brain dysfunction (including reducing the risk for Alzheimer's disease (AD)), results from the Women's Health Initiative (WHl) have suggested the contrary and left the field unsettled as to the future of hormone therapy. However, important caveats of the WHl include the possibility that the duration of postmenopausal hormone deprivation diminish the protective brain response to steroid hormones, suggesting the concept of a finite therapeutic window of opportunity for estrogens and/or progestins. During the first period (4 years) of funding, this Program Project sought to identify and characterize new and alternative mechanistic targets through which estrogens and progestins affect the brain. The intent was to achieve a broader perspective on the neurobiology of steroid hormones and a better conceptual understanding of how these hormones protect the brain from insults relevant to age and age-associated diseases such as AD. These studies were successful and showed that membrane progesterone receptors, a mitochondria localized estrogen receptor, and intracellular Ca2+ channels (IP3 receptors and Ryanodine receptors) are key targets for estrogens and/or progesterone (P4), particularly within the context of brain protection. In this competitive renewal, we propose to apply our findings from the first period of funding to test our overall hypothesis that the expression and/or function of these novel targets dictate the sensitivity of the brain to the protective effects of estrogens and P4, and therefore define the critical window of therapeutic opportunity. Our team of researchers will address the overall hypothesis by integrating their respective Project-specific analyses (which themselves have common themes, such as hormone-induced cell signaling) into a common animal model (the OVXed rat, enabled by Core B), and then translating the results into human samples (brain samples from surgically menopausal women and their respective controls - enabled by Core A). Successful completion of the studies proposed will serve as the framework for defining strategies to expand the therapeutic window. That is, interventions that help maintain the expression and/or function of progesterone receptors, mitochondrial ER and intracellular calcium channels may help maintain the brain's capacity to respond to estrogen and P4. Together, these strategies will lead to the development of safer and more effective therapeutic strategies for treating the menopause and reducing the risk for various brain disorders (including AD) whose risk increases during the post'-menopausal period.